Medical treatment in acromegaly

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Abstract

Acromegaly is a rare disabling disorder that results in premature death. The excess mortality and morbidity are the result of prolonged elevation of growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels, and vigorous control of these improves well-being and restores life expectancy to normal. Recognition of the benefits of treatment has emphasised the need for optimal control of the GH/IGF-I axis. Transsphenoidal surgery is first-line therapy in the majority of patients; however, as most tumours are macroadenomas, cure rates are low. The role of radiotherapy is evolving and, although extremely effective at controlling tumour growth, it can take up to 15 years to control GH & IGF-I levels. In the interim, medical therapy is necessary. Dopamine agonists are inexpensive oral agents but, although most patients experience some benefit, GH and IGF-I levels are only normalised in around 35–40% of patients, and side effects are common. Somatostatin analogues are the gold standard of medical treatment. They can induce tumour shrinkage in a proportion of patients and can normalise the GH/IGF-I axis (at best) in approximately 65% of individuals; however, this leaves a significant cohort uncontrolled. The advent of the GH receptor antagonist pegvisomant provides the potential for IGF-I to be normalised in virtually every patient, but this novel form of therapy, which does not act on the pituitary, also raises many questions.

Introduction

Acromegaly is a rare disfiguring condition caused by growth hormone (GH) hypersecretion usually from a pituitary somatotroph adenoma. A single GH molecule binds two identical cell-surface receptors, inducing dimerisation and stimulating production of insulin-like growth factor-I (IGF-I), which is the effector of many of the actions of GH. IGF-I is generated in many tissues and has endocrine, paracrine and autocrine actions, with circulating IGF-I being predominantly of hepatic origin (Figure 1). The morbidity and excess mortality of acromegaly are the consequence of the metabolic actions of excess GH and IGF-I secretion rather than the mass effects of the pituitary tumour, and result in the many signs and symptoms of the disease, such as lethargy, sweating, arthralgia, hypertension and diabetes mellitus. The risk of premature death is increased two- to fourfold [1]. Recent advances in medical therapy have raised the prospect of obtaining biochemical control in virtually every patient, with consequent relief of symptoms and restoration of life expectancy to normal.

Transsphenoidal surgery is the treatment of choice for most patients, with the outcome dependent on the size and invasiveness of the tumour and, in particular, the skill of the specialist pituitary surgeon. As 70% of tumours are macroadenomas, most patients are not cured by surgery and require medical treatment [2]. Radiotherapy is an option, either conventional three-field or stereotactic, but the full benefit is not seen for many years, which again necessitates medical therapy in the interim. For the past decade, the mainstay of medical treatment has been dopamine agonists and somatostatin analogues, with the latter being the gold standard against which the recently available GH receptor antagonist pegvisomant must be judged. Controlled trials have reported pegvisomant to have a superior ability at achieving biochemical disease control, but many questions about this new form of therapy remain. This review focuses on the medical therapy of acromegaly and considers the role of pegvisomant.

Section snippets

Dopamine agonists

The first effective medical treatment for acromegaly was the dopamine agonist bromocriptine, which lowers GH secretion in most patients but only achieves the desired levels of control in less than 20% of cases [3]. Alternative dopamine agonists include cabergoline and quinagolide, which have a prolonged duration of action and greater efficacy, and are also better tolerated. The largest study of cabergoline in acromegaly was conducted in 64 patients (16 with prolactin co-secreting tumours), of

Somatostatin analogues

Somatostatin analogues are the most widely prescribed medical treatment for acromegaly, usually as adjunctive therapy to surgery and/or radiotherapy but increasingly as primary therapy. Octreotide and lanreotide are cyclic octapeptide somatostatin analogues that have been in use for many years, although the latter is not available in the USA (Figure 2). Their inhibition of GH secretion is predominantly mediated via somatostatin receptor-2 and -5 subtypes expressed on the adenoma. Octreotide was

Growth hormone receptor antagonists

Pegvisomant is a GH analogue and novel form of pharmacotherapy for acromegaly. GH is a 22 kDa peptide (191 residues) that contains two disulfide bonds and four α–helices. GH acts by binding two identical cell-surface receptors to induce functional receptor dimerisation and thereby trigger second messengers and IGF-I generation. Gly120 in the third α-helix of human GH is critical for the binding of the second GH receptor, and substitution of this amino acid with a side-chain creates a GH

Conclusions

Surgery is the treatment of choice in the majority of patients with acromegaly, as it offers the prospect of rapidly lowering GH levels and a subsequent cure, as well as being cost-effective. The availability of pegvisomant will not greatly alter the use of dopamine agonists as therapy, as the advantages of these drugs are oral administration and cost. However, pegvisomant does represent a major advance in the treatment of acromegaly and will impact on the use of somatostatin analogues, which

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